JPS6039676B2 - Process for producing chromonyl-substituted propionic acids and their esters - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel chromonyl-substituted propionic acids and methods for producing their esters. 6"(2-phenylchromonyl)acetic acid is known, and this compound has been described in "Jom Asahi of the Indian Ch.
ty”50 295-8 (197
3), and the applicant has discovered its bile secretion effect. The inventors have now discovered new compounds that have significant analgesic and anti-inflammatory properties and are only slightly inflammatory. The novel chromonyl-substituted propionic acid and its ester produced by the present invention are represented by the following general formulas (1) and (0), respectively: In the above formula, x is phenyl,
substituted phenyl, furyl or chenyl group, the substituent of the substituted phenyl group is at least one halogen, preferably chlorine, lower alkyl, preferably methyl, trihalomethyl is an aryloxy group; R is lower alkyl, dialkyl Amino lower alkyl, -hydroxy lower alkyl or morpholinoethyl group. The chromonyl-substituted propionic acid of the present invention can also be in the form of a salt with an inorganic or organic salt group, and the ester containing a basic group of chromonyl-substituted propionic acid can be in the form of a pharmaceutically acceptable addition salt. You can also take Propionic acid of formula (1) can be prepared from the corresponding methyl ester of acetic acid, which is converted to the corresponding ethyl malonate by treatment with ethyl carbonate and sodium hydride. Upon completion of the transesterification reaction, a carbanion is obtained in an alkaline soot, which is then alkylated with methyl iodide in dimethylformamide. When this alkylated product is treated with a mixture of acetic acid and hydrochloric acid, the two ester functions are hydrolyzed and the resulting malonic acid undergoes decarboxylation. The reaction process is as follows. The acetic acid derivative as a starting material has the formula: (wherein or from 0-hydroxyacetophenone. Each method consists of five steps, three of which are common to both. Process A5-Methyl-2-hydroxyacetophenone is condensed in the presence of sodium hydride with ethyl carboxylate of group Cyclizes to chromone. The 5-methyl group of the original acetophenone is then converted to the corresponding carboxymethyl group by bromination with N-bromosuccinimide (N mother), treatment with an alkali metal cyanide, and subsequent acid hydrolysis. Method B 5-methoxymethyl-2-hydroxyacetophenone obtained from the corresponding chloromethyl compound is condensed with the ethyl carboxylate of group X in a dry aromatic solvent or dimethyl sulfoxide in the presence of sodium hydride. The dibenzo-11ylmethane obtained is cyclized with hydrobromic acid to give the corresponding bromomethylchromone, which is then treated with alkali cyanide and acid hydrolyzed. formula(
The propionic acid ester of 0) can be prepared by known methods, in particular by reacting the corresponding acid with an alcohol ROH (R is a lower alkyl, lower -hydroxysulkyl, lower dialkylaminoalkyl or morpholinoethyl group) or by reacting the acid with It can be produced by reacting a sodium or potassium salt with an alkyl halide. The pharmaceutical analgesic effect, anti-inflammatory effect, and some concentration effects of propionic acid of formula (1) and propionate ester of formula (D) (hereinafter referred to as compounds according to the present invention) were determined by various methods. The compound names are shown by the example numbers below. The analgesic effect of the compounds according to the present invention was evaluated using the acetic acid test method (Kos) on mice.
terAnde on & De is shown by the method of Siegm skin d modified by er. 50% effective dose ED5 determined for several compounds. (female/k9) are shown in Table 1 below (aspirin and flavonyl-6-acetic acid are shown as control examples). The anti-inflammatory effects of the compounds in Table 1 are particularly demonstrated in the carrageenin-induced water abdominal test (PrM.S ratio. Exp. Biol.
Med, Vol. M, pp. 544-54 (1962)). The results obtained for several compounds are shown in Table 0 below (phenylptazone and flavonyl-6-acetic acid are shown as controls). Table □ Compounds according to the invention were compared with phenylbutazone to evaluate their loss field effect. The method used was to aggravate the disease caused in the rat's body by the method described in "Castroenterology", Vol. 5, pp. 43-61 (1945). Table m, which shows the results obtained with two preferred compounds according to the invention, shows the advantages of these compounds. Table m Pharmacological silk compositions containing as active ingredient a compound according to the invention in the form of a base or a corresponding organic or inorganic salt, such as tablets, pills, capsules, lozenges, aqueous suspensions, injections, counterfeit liquids, Sh. It can be in the form of a cup or the like. Tablets can, if desired, be made resistant to gastric juices by coating with cellulose derivatives. Pharmaceutical compositions comprising a compound according to the invention as an active ingredient and a physiologically acceptable solid or liquid pharmacological excipient or diluent are administered in an amount of 20 to 1000 9 per day for said active ingredient. It is possible. In the clinical trial using the compound of Example 13, the following items were observed. Observations 1 Female G (607) - Left knee arthritis after fracture The left knee improved by administering the compound of Example 13 as an active ingredient and 4 tablets of 100 9 per day for 10 days. The bending degree is from 1y to 25o.
recovered. Adequate analgesic effects were observed and the drug was well tolerated. Observation 2 Male Day (21 years old) - Pseudoarthritis of the knee 5 100P tablets were administered per day for 8 days Example 1
Treatment with the active ingredient No. 3 relieved the pain for 3 hours and had a very good anti-inflammatory effect. It also had perfect customer resistance. Observation 3 Female F (47 years old) - venous cancer removal from left leg 1 per day
Treatment with the active ingredient of Example 13 by administering 6 00 female tablets for 5 days resulted in complete relief of pain within 30 minutes after administration, and this effect lasted for 3 hours. The customer resistance was also extremely good. Observations 4 Male R (
35 years old) - Radicular type right lateral sciatica Treatment with the active ingredient of Example 13 by administering 4 100P tablets per day for 10 days resulted in Lasegue test results of 450 to 750 improved. The analgesic effect was good and the patient tolerance was perfect. Observation 5
Female M (48A) Severe neck pain from one joint bran Example 13
By administering 4 of 100 9 tablets per day containing the active ingredient for 8 days, the patient was able to exercise his neck at normal amplitude without pain. The analgesic effect was good and the customer tolerance was also very good. In the clinical trial using the compound of Example 22, the following items were observed. Observations 1 Male J (797) - Severe pain on the right side of the neck and arm The pain and inflammation were treated by administering 4 150 9 tablets per day containing the active ingredient of Example 22 for 8 days. Very good results were obtained. It was also completely tolerated. Observation 2 Male S (4Zgi) - Severe lower back pain Treatment with 4 150 female tablets containing the active ingredient of Example 22 per day for 10 days resulted in significant improvement and the patient could no longer touch his fingertips. The distance it can move relative to the ground has been reduced from 40 to 5. The analgesic effect was good and the customer tolerance was perfect. Observations 3 Male M (6Z years) - Arterial inflammation of the lower limbs 150 9 tablets containing the active ingredient of Example 22 4 per day
Treatment by administering the drug for 5 days resulted in significant relief within 3 minutes after administration, and the effect lasted for more than 3 hours. Customer durability was also satisfactory. Observations 4 Male B
(24 years old) - Removal of left kneecap Completely rapid (30
(within minutes) and long-lasting (>3 hours) pain relief was achieved. It was also well tolerated. Observations: 5 Female C (56 Gi)
- Painful lower back arthropathy in both hips treated by administering 6 150 nail o tablets per day containing the compound of Example 22 for 10 days, resulting in significant improvement within 3 minutes after administration. Relief was obtained and this effect lasted for 3 hours. It also had perfect customer resistance. Next, the present invention will be further explained by examples. However, Examples 1 to 10, Examples 1 &
Example 20 and Example 33 are reference examples illustrating the production of starting compounds for the process of the present invention, of which Example 1 follows Method A and the others follow Method B. Examples 11-1
7. Example 19 Examples 21-22 and Examples 34-35
is an example of the production of chromonyl-substituted propionic acid according to the method of the present invention (Example 11 is combined with Example 22, and Example 12 is combined with Example 13, each showing an example of the production of a single-purpose compound), Examples 23 to 32 illustrate the preparation of various corresponding esters from chromonyl-substituted propionic acids. Example 16-[2-(4
'-chlorophenyl)chromonyl]acetic acid This compound can be prepared by method A via the following intermediate: {a} 2
'-Hydroxy-5-methyl-4'-chlorodibenzoylmethane Empirical formula: C, 6 days, 3CI03; Molecular weight = 28
8.5 Into a dry reactor were added 50% sodium hydride (32 moles), anhydrous benzene (200 moles), and 61.59 moles (0.33 moles) of ethyl parachlorobenzoate.
I entered it. The mixture was refluxed and 33.3 parts of 5-methyl-2-hydroxyacetophenone (0.3 parts) in 10 parts of dry benzene was added.
A solution of 22 mol) was added dropwise over a period of 3 hours. Refluxing was continued for 3 hours after the addition was complete. The reaction mixture was then cooled using an ice bath and 50M ethanol was added. The solvent was evaporated under reduced pressure using an aspirator on a water bath and the pasty residue was dissolved in 30% acetic acid 400%.

[Naka Hinahai Shitsu] Dissolved in 1 hour. The product was filtered and dried, and the resulting dibenzoylmethane compound was recrystallized from 100% ethanol. Melting point = 136-7°C; Yield = 27.8 nights (44%, theoretical yield = 63.3 nights). {b' 6-Methyl-2-(p-chlorophenyl)chlorophenyl Empirical formula: C, p, . 02CI; molecular weight=270.
22.5 mol (0.095 mol) of dibenzoylmethane obtained in step 5'a}, 225 ml of glacial acetic acid, and 22 mol of concentrated sulfuric acid.
．． 5' was charged into the flask. The mixture was refluxed for 1 hour, cooled, and poured into an ice-cold 800ml tube. The resulting white solid was heated in a furnace, washed with water, and immediately recrystallized from ethanol. Melting point = 190°C; Yield = 15.5 nights (73%, theoretical yield 21.1 nights). tc}
6-Bromomethyl-2-p-chlorophenylchromone Empirical formula: C, 6 days, CIQ; Molecular weight: 361.56
-Methyl-2-(p-chlorophenyl)chromone17.
5 (0.065 mol), N-promosuccinimide 1
1.6 mol (0.065 mol), 700 mol of carbon tetrachloride and 0.1 mol of azopisisobutyronitrile) 6
Refluxed for an hour. The solvent was then evaporated and the resulting solid residue was recrystallized from ethyl acetate. Melting point = 198 qo; Yield: 8.8 qo (
39%, theoretical yield = 22.75 evening). {d) 6-cyanomethyl-2-(p-chlorophenyl)chromone empirical formula:
C, 7 days, oCIN02: molecular weight = 295.71 water 50
A reaction vessel was charged with 3.2 moles (0.05 mol) of potassium cyanide dissolved in [1], and the solution was heated to 60 qo, followed by 8.3 moles (0.0 mole) of 6-furomomethyl-2-(p-chlorophenyl)chromone dissolved in .023 mol) of ethanol 1
600' solution was added every 20 minutes in 4 portions. After the addition was completed, the mixture was refluxed for 3 hours, dried and dissolved in water. The obtained solid was separated by furnace and recrystallized from alcohol. Yield = 5 days (72%, theoretical yield = 7 days); Melting point = 21 points Elemental analysis: Calculated value Actual value C% 69.03 69.05 H% 3.43 3.40 N% 4.75 4. 73 (e} 6-(2-p-chlorophenylchromonyl)acetic acid Empirical formula: C, 7 days,.CI04: Molecular weight = 314.7
22-(p-chlorophenyl)-6-cyanomethylchromone 4.7 parts (0.015 mol), concentrated sulfuric acid 10 parts, water 1 part
A solution of 0.0 ml and 10 ml of glacial acetic acid was refluxed for 2 hours, then the mixture was poured into 60 ml of ice water. The precipitated desired acid was purified by formation of its sodium salt and recrystallization from dioxane to give a white solid. Yield = 3 yen (65%, theoretical yield 5.4 yen); Melting point = 24〆0
Elemental analysis: Calculated value Actual value C% 64. Spot 64.85 H% 3.52 3.58 Example 2 6-(2-○-chlorophenylchromonyl)acetic acid This compound can be prepared by method B using the following intermediate:
[a} 2″-chloro2′-hydroxymethoxy-5
'-Methyldibenzoylmethane Empirical formula: C, 7 days, 5C
I04; Molecular weight F318.5 This compound is prepared from 6-methoxymethyl-2-hydroxyacetophenone,
It is produced from 5-chloromethyl-2-hydroxyacetophenone as follows. 5-chloromethyl-2-hydroxyacetophenone 16
60 moles (9 moles), methanol 13.5 moles and concentrated hydrochloric acid 9 moles
40' of refluxed, powdered 98% iron 1
512 grams (27 grams atoms) were added in 2 hours. Then reflux 1. The mixture was allowed to stand overnight. The iron was separated into a furnace, the furnace liquid was concentrated to 5 ml, and neutralized with 1800 ml of sodium bicarbonate dissolved in 10 ml of water. The resulting reaction mixture was extracted with 10.5 sleeves of benzene, the benzene was removed under reduced pressure, and the product was isolated by distillation to yield a colorless oil. Boiling point 100 - 103 qC/0.3 Hg; yield 1232 m = 72% (theoretical yield = 1620 m). 50% sodium hydride in mineral oil (0. paper moles), 0
-36.5 mols of ethyl chlorobenzoate (0.20 mol),
2-Hydroxymethoxy-5-methylacetophenone 2
The condensation was carried out according to the method described in Example 1' using 300 ml (0.13 mol) and anhydrous benzene 225 ml. The resulting dibenzoylmethane was isolated as a solution in 30% acetic acid and purified by recrystallization from 200' of isopropanol to give a yellow solid. Melting point = 95oC: Yield 2
6.3 evenings = 62% (theoretical yield: 42.5 evenings). 'b)6
-furomomethyl-2-(o-chlorophenyl)chromone Empirical formula: C, 6 days, prCI02: Molecular weight = 349.6
22''-chloro-2'-hydroxy-5'-methoxymethyldibenzoylmethane 26 (0.082 mol),
66% hydrobromic acid 7 and 104' of glacial acetic acid were refluxed for 3 hours. The reaction mixture was then poured into ice water, and the solid separated was filtered out, washed with water, and recrystallized from acetone. Yield 17.
4 nights = 63% (theoretical yield = 28.5 nights); melting point = 91°C
. Elemental analysis: Calculated value Actual value C% Hiroshi. 97 54. Based on H% 2. 2.90 Br% 22.86. 82 [c-2-(o-chlorophenyl)-6-cyanomethylchromone Empirical formula: C, 7 days, oCIN02: Molecular weight =
295.71 This compound was converted into 6-furomomethyl-2-(o
-chlorophenyl) - chromone 5 moles (0.0143 mol), cyanide chlorium 1.56 moles (0-0286 mol)
, 200 parts of ethanol and 10 parts of water according to the method of Example 1 [d']. The resulting white solid was recrystallized from 50% ethanol. Yield 3.3 evenings = 66% (theoretical yield = 4.3 evenings). Melting point 131-13〆0. Elemental analysis: Calculated value Actual value C% 69.05 69.01 H% 3.40 3.43 N% 4.73 4.77 CI% 11.99 12.03 (d) 6-(2-o-chlorophyll) enylchromonyl)acetic acid Empirical formula: C, 7 days, . CI04; molecular weight = 314.72
The mixture of 2-(o-chlorophenyl)-6-cyanomethylchromone (29.5 molar) (0.1 mol), 68 molar of glacial acetic acid and 68 molar water was refluxed for 3 hours, then the reaction mixture was diluted with ice water and 88 molar water.
The solid separated was filtered. This was then dissolved in a hot 5% sodium bicarbonate solution of 700'
The solution was dissolved in a furnace, acidified with hydrochloric acid, and recrystallized from ethyl alcohol to give a white solid. Melting point 217-21
Grade 0: Yield 27 evenings = 90% (theoretical yield = 31.4 evenings).
Elemental analysis: Calculated value Actual value C% 64. Iso 64.90 H% 3.52 3.56 CI% 11.27 11.29 Example 3 6-(21m-(chlorophenyl)chromonyl)acetic acid This compound was prepared in the same manner as in Example 2. The isolated intermediates are: (a) 3''-chloro2'-hydroxy-5'-methoxymethyldibenzoylmethane Empirical formula: C, Rainbow 7CI04: Molecular weight = 31
8.5 Melting point of the yellow solid obtained: 860, yield 44%. 'b) 6-furomomethyl-2-(m-chlorophenyl)
-Chromone empirical formula: C, 6 days, Nin rCI02; molecular weight =
349.52: Melting point of the obtained white solid = 16 (acetone); Yield = 71%. 'c} 2-(m-chlorophenyl)-6-cyanomethylchromone Empirical formula: C, 7 days, oCINQ; Molecular weight = 2
95.71; Melting point of the obtained white solid = 195-6°C (
ethanol); yield = 56%. Elemental analysis: Calculated value Actual value C% 69.05 69.02 H% 3.40 3.40 N% 4.73 4.7・5 {d} 6-(21m-chlorophenylchromonyl)acetic acid experiment Formula: C, 7th, . CI04: Molecular weight = 314.7
2: Melting point of bound white solid = 2 °C (ethanol):
Yield rat%. Elemental analysis: Calculated value Actual value C% 64.88 64.85 H% 3.53 3.50 CI% 11.27 11.30 Example 4 6-(m-trifluoromethyl-12-phenylchromonyl) Acetic acid This compound was prepared by Method 8. The isolated intermediate is: {a} 2-Hydroxy-5'-methoxymethyl-3''-trifluoromethyldibenzoylmethane Empirical formula: C, 8 days, 4F304:
Molecular weight = 351: Melting point of the obtained yellow solid = 128qC
(Ethanol); Yield 73% 'b' 6-furomomethyl-2-m-trifluoromethyl-phenylchromone Empirical formula: C, 7 days, Core rF302: Molecular weight = 383 Melting point of the beige solid obtained: 1 Spot 00 (acetone); yield =
72% [c) 6-cyanomethyl-2-trifluoromethylphenylchromone empirical formula = C, 8th, J3N02;
Molecular weight = 329: Melting point of the obtained white solid = 15200
(Eta/R); Yield = 36% (d) 6-(2-m-trifluoromethylphenylchromonyl)acetic acid Empirical formula: C
, 8th,. F304; Molecular weight = 348.29; Melting point of obtained white solid = 195oo (ethanol); Yield = 6
2% elemental analysis: Calculated value Actual value C% 62.08 62.05 H% 3.18 3.21 F% 16.36 16.39 Example 6 6-(2-p-fluorophenylchromonyl) Acetic acid This compound was prepared by method B described in Example 2. The isolated intermediate is: (a} 4″-fluoro-2-hydroxy-5-methoxymethyldibenzoylmethane Empirical formula: C, 7 days, 04; Molecular weight = 303:
Melting point of the resulting yellow solid = 1 °C (diSof.ropyether); Yield = 50% {b} 5-furomomethyl-2-(p-fluorophenyl)chromone Empirical formula:
C, 6 days, F02; molecular weight = 333.17; melting point of the obtained white solid = 151°C (acetone): yield = 45
% elemental analysis: Calculated value Actual value C% 57. Iso 57.73 H% 3.02 3.04 Br% 23.09 24.05 F% 5.70 5.73 'c} 6-cyanomethyl-2-p-fluorophenylchromone Empirical formula: C, 7 days , BuFQ; molecular weight = 279:
Melting point of the obtained white solid = 20 o(ethanol); Yield = 54% {d) 6-(2-p-fluorophenylchromonyl)acetic acid Empirical formula: C,? Day,. F04: Molecular weight =
2 spots. 27; Melting point of the obtained white solid = 22yo (ethanol); Yield = 80% Elemental analysis: Calculated value Actual value C% Line. 45 Muscle. 48 H% 3.71 3.80 F% 6.37 6.39 Example 6 6-[2-(2'-thienyl)chromonyl]acetic acid This compound was prepared in the same manner as in Example 2. The isolated intermediates are: (a) 1-(2'
-hydroxy-5'-methoxyphenyl)-3-(2''
-thienyl)-1,3-dioxypropane Empirical formula: C,
5th, 1,000 S04: Molecular weight = 290: Melting point of the obtained white solid: 90% (isopropanol); Yield = 50%'
b'6-furomomethyl-2-(Q-thienyl)chlorothenyl Empirical formula: C, 4 days 9Br02S; Molecular weight = 321: Melting point of the white solid obtained = 179 qo (acetone); Yield = 42% {c1 6-cyanomethyl -2-(Q-thienyl)crosensanine Empirical formula: C, Xin902NS; Molecular weight = 2
67.311 Melting point of white solid obtained = 202°C (ethanol nodioxane 7:3 mixture); Yield = 68%
'd'6-[2-(2'-chenyl)chromonyl]acetic acid Empirical formula: C, 5 days, oS04: Molecular weight = 286.311
Melting point of the obtained white solid = 205qo (ethanol);
Yield = 73% Elemental analysis: Calculated value Actual value C% 62.92 62.86 H% 3.52 3.59 S% 11.20 11.23 Example 7 6-[2-(2-furyl)chromonyl ] Acetic acid This compound was prepared by method B described in Example 2. The intermediates obtained are: 'a) 1-(2'-
Hydroxy-5-toxymethylphenyl)-3-(2
″-furyl)-1,3-dioxopropane Empirical formula: C,
5th, 405: Molecular weight = 274: Melting point of the obtained yellow mass = 73oo (hexane): Yield = 73%'b'6-furomomethyl-2-(2'-furyl) clousan Empirical formula:
C, 4 days 9Br02; Molecular weight = 289 Production point of the obtained white solid = 1 m C (ethanol); Yield = 56% (c'6
-Cyanomethyl-2-(2'-furyl)chromone Empirical formula: C, 5 days 9N02: Molecular weight: 251: Melting point of the obtained white solid = 210 qo (ethanol): Yield = 50% {
d} 6-[2-(2'-furyl)chromonyl]acetic acid Empirical formula: C, 5 days. 05; Molecular weight = 270.25 Melting point of the obtained white solid:
198°C (ethanol): Yield = 65% Elemental analysis: Calculated value Actual value C% 66.66 66.69 H% 3.73 3.68 Example 8 6-(2-Methylchromonyl)acetic acid This compound Produced by the method described in Example 2. The resulting intermediate is as follows: (a} 1-(2-hydroxy-5'-methoxymethylphenyl)-1.3-
Dioxobutane empirical formula; C, 2 days, 404: Molecular weight = Pine 2; Melting point of the pale yellow solid obtained = 8 pi 0 (diisopropyl ether): Yield = 30% (b'6-bromomethyl-2-methyl Chromone empirical formula: C,.902Br: Molecular weight = 253: Melting point of the obtained white solid: 13200 (Ethanol/Water 1:1) [c) 6-cyanomethyl-2-methyl Chromone Empirical formula: C,2 902N; molecular weight = 19
9: Melting point of the obtained white solid = 12 is 0 (isopropanol); Yield = 53% {d} 6-(2-methylchromonyl)acetic acid Empirical formula: C, 2 days. 04: Molecular weight = 218.212: Melting point of the obtained white solid = 19200 (ethanol): Yield = 51% Elemental analysis: Calculated value Actual value C% 66.05 65.99 H% 4.62 4.65 Implementation Example 9 6-(2-(3'-chenyl)chromonyl]acetic acid This compound was prepared by the method described in Example 2. The isolated intermediate is: 'a} 1-(2'-Hydroxy-5'-methoxymethylphenyl)-3-(3'-thienyl)-1,3-dioxopropane Empirical formula: C, 5 days, 4S04; Molecular weight = 2
90 The yellow solid obtained was directly carried out in step 'b' without purification.
It was used in {b'6-Bromomethyl-2-(8-thienyl)chlorosensanine empirical formula; C, 4 days 9Br02S; molecular weight = 321;
Melting point of the obtained white solid = 160 qo (ethanol);
Yield = 32%'c} 6-Cyanomethyl-2-(8-thienyl)chlorothenyl Empirical formula: C, 5 days 902NS; Molecular weight = 267.319: Melting point of the obtained white solid = 192
°C (washed in ethanol); Yield = 74% [d} 6-
[2-(3'-chenyl)chromonyl]acetic acid empirical formula: C
, 5th,. 04S: Molecular weight = 286.311: Melting point of obtained white solid = 207-8°C (ethanol): Yield = 30% Elemental analysis: Calculated value Actual value C% 62.92 62.86 H% 3.52 3 .48 S% 11.20 11.18 Example 10 6-[2-[2-(5'-chlorothienyl)]chromonyl]acetic acid This compound was prepared in the same manner as in Example 2. The isolated intermediate is: {a} 11 (2÷
Hydroxy-5'-methoxymethylphenyl)-31 [
2″-(5″-chlorothienyl)]-1,3-dioxopropane Empirical formula: C. 5th, 304SCI: molecular weight = 3
24.5: Melting point of the obtained solid = 10 is C (diisopropyl ether): Yield = 69% (b) 6-furomomethyl-21 [Q1 (5'-chlorothienyl)] chromone empirical formula; C , 4 days 8BrSCI03: Molecular weight = 355.5:
Melting point of the obtained white solid = 18000: Yield = 76%. {c) 6-cyanomethyl-2-[2'-(5-chlorothienyl)]chromone Empirical formula: C, 5 days, 8 NO; molecular weight: 301.5; melting point of the obtained white solid: 210 hours (
dioxane); yield = 50%. {d)6-[(2'-(5'-chloro.thienyl-2)]chromonyl]acetic acid Empirical formula: C, 5 days 9
CI04S: Molecular weight = 320.74; Melting point of the white solid obtained = 226-7°C (dioxane): Yield = 70%. Elemental analysis: Calculated value Actual value C% 56.17 56.13 H% 2.82 2.99 CI% 11.06 10. Team Example 16 Methyl-6-flavonyl acetate Empirical formula: C, 8 days, 4: Molecular weight = 29 6-Flavonyl acetic acid 5.2 hours (0.0186 mol), concentrated sulfuric acid 3.7 [and anhydrous methanol] The mixture was refluxed for 7 hours. The reaction mixture was then poured onto 140 ml of ice water, and the desired ester precipitated was washed with sodium bicarbonate solution and water. Yield = 4.45 min = 81% (theoretical yield = 5.45 min) Melting point: 117q0 (methanol). Elemental analysis: Calculated value Actual value C% 73.45 73.48 H% 4.79 4.82 Example 12 Methyl-6-[2-thienyl)chromonyl]acetate Empirical formula: C. 6th day, Bu04; Molecular weight = 300.
3mu6-[2-(2-thenyl)chromonyl]acetic acid 30
In the evening (0.105 mol), 400 ml of anhydrous methanol and 21 ml of concentrated acid were refluxed for 7 hours, then the mixture was cooled and poured into 1 ml of water. The obtained precipitate was heated in a furnace, dried, and recrystallized from methanol 200 ml. Yield = 25.8 nights = 83% (theoretical yield = 31.5 nights) Melting point = 106-700. Elemental analysis; Calculated value Actual value C% Strain. 99 6377 H% 4.02 4.28 S% 10. Total 10.69 Example 13 Ethyl 2-[2-(Q-thienyl)-6'-chromonyl]propionate {a} 2-(2-[Q-thienyl]
-6-Chromonyl)-2-methylmalonate Empirical formula: C
2, day 2. 06S; Molecular weight = 400.23 A suspension of 72% sodium hydride (0.27 mol) in key oil was heated to boiling point with 550 ml of ethyl carbonate. Next, methyl-6-[2-(Q-
chenyl) chromonyl] acetate 73.5 units (0.2
45 mol) was added dropwise and refluxing was continued for a further 2 hours after the addition was complete. The mixture was then cooled to 200 ml of methyl iodide.
A solution of 3 (0.6 mol) in dimethylformamide 240M was quickly added. The reaction mixture was heated at room temperature for 1
After stirring for a while, the solvent was distilled off under reduced pressure. The residue was dissolved in water and extracted with benzene, the organic phase was separated and dried, the benzene was distilled off under reduced pressure and the residual oil was crystallized from diisopropyl ether. Yield = 82%: Melting point = 90°C (diisopropyl ether). Elemental analysis: Calculated value Actual value C% 63.00 62.75 H% 5.03 4.95 S% 8.00 7.90 NMR (deuterochloroform) 6 (ppm) From tetramethylsilane reference material H: 1 .35 (triplet J=7c
ps) Mother H: 2.0 (singlet) 4H: 4.35 (quartet J = 7 cps) IH: 68 (singlet) Fine: 7.1 to 8.4 (multiplet) 'b) 2- [2'-(Q-thienyl)-6'-chromonyl]propionic acid Empirical formula: C, 6th, evening 04: Molecular weight = 300.31 ethyl-21 [2'-(Q-thienyl)
-6'-chromonyl]12-methylmalonate 809 (
A solution of 400% of acetic acid (0.2 mol) and 200% of concentrated hydrochloric acid was refluxed for 7 hours, then cooled to 10 °C, and the resulting acid was filtered. This was purified by washing with water, dissolving in hot sodium bicarbonate solution, and refluxing with animal black. The product was stirred and acidified with concentrated hydrochloric acid, then filtered and quickly crystallized from acetic acid to give a pale yellow solid. Yield = 75%; Melting point = 255-260q0 Elemental analysis: Calculated value Actual value C% 63. Spot 64.09 H% 4.03 4.03 S% 10. Iso ] 0.69 NMR (DMS○d6) 6 (ppm) Reference substance Tetramethylsilane 9H: 1.5 (double J = 7 cps) IH: 3.95 (quartet i = 7 cps) IH: 7 ( Singlet) IH: 7.25-7.50 (multiplet) 2H: 7.75-7.90 (multiplet) 2H: 8-8.25 (multiplet) IH: 12-13 (broad peak) Implementation Example 14 Methyl 2-[2'-(Q-furyl)-6-chromonyl]propionate (a) 6-[2-(Q-furyl)-chromonyl]acetate Empirical formula: C, 6 days, 205: Molecular weight = 2 I. A solution of 14.4 mol (0.053 mol) of 266-[2-(2-furyl)chromonyl]acetic acid (see Example 7) in 200 ml of anhydrous methanol and 12 ml of concentrated sulfuric acid was prepared.
Refluxed for an hour. The solution was then cooled and poured into water, and the resulting precipitate was filtered, dried and recrystallized. Yield = 70%, melting point = 11
70 (methanol). Elemental analysis: Calculated value Actual value C% 67.62 67.45 H% 4.25 4.15 {b} Ethyl 2-[6-(2-Q-furylchromonyl)]-2-methylmalonate empirical formula :C2. Day 2. 07; Molecular weight = total 4.37 This compound was converted from the ester of Step {a- to Example 13

[Produced in the same manner as a'. A pale yellow solid was thus obtained. Yield = 70%: Melting point =
Iso℃ (diisopropyl ether). Elemental analysis: Calculated value Actual value C% 65.62 65.80 H% 5.24 5.15 NMR (deuterochloroform) 6 (ppm) Reference substance Tetramethylsilane fine: 1.3 (triplet J=7c
ps) Pan: 2.0 (singlet) Cape: 4.3 (quartet J: 7 cps) IH: 055~6.7 (multiplet) IH: 6.75 (singlet) Spot: 7.1~ 8.4 (Multiplet) {c} 2-[2'-(Q-furyl)-6-chromonyl]propionic acid Empirical formula: C, 6 days, 205: Molecular weight = 2
Shigeru. 26ethyl 2-(2(Q-furyl)-6-chromonyl)-2-methylmalonate 5.5 yen (0.0143
A solution of 28 moles of acetic acid and 14 moles of hydrochloric acid was refluxed for 7 hours. A white solid was obtained by performing separation and purification in the same manner as in Example 13'b'. Yield = 60%: Melting point = 210-215% (isopropanol). Elemental analysis: Calculated value Actual value C% 67.60 67.57 H% 4.25 4.25 NMR (DMS0d6) 6 (ppm) Reference substance Tetramethylsilane general: 1.5 (doublet J = 7 cps) IH : 4.0 (Quadrut J = 7 cps) IH: 6.65 (around singlet) IH: 6.8 to 7 (multiplet) Spot: 7.5 to 8.2 (multiplet) IH: 12.4 ~13 (broad peak) Example 15 2-[2'-(8-thienyl)-6-chromonyl]propionate (a) Methyl[2'-(8-thienyl)-6'
-Chromonyl]Acetate Empirical formula: C, 6th, 204S
: Molecular weight=300. Paper This compound was prepared similarly to Example 14 {a}. Melting point of the obtained white solid = 11rC: Yield = 93% NM
R (deuterochloroform) 8 (ppm) reference substance
Tetramethylsilane 9H: 3.8 (singlet) IH: 6.8 (singlet) Fine: 7.4-8.3 (multiplet) 'b} Ethyl 2-[2'-(P-thienyl)- 6-
Chromonyl]-2-methyl malonate Empirical formula: C2,
Day 2. 06S: Molecular weight = 400.4 This compound was converted into methyl [2-
Prepared analogously to Example 13al starting from (8-thienyl)-6-chromonyl]acetate. Melting point of the obtained white solid = 9yo: Yield = 60% Elemental analysis: Calculated value Actual value C% 63.00 62.83 H% 5.03 4. Group S% 8.00 8.10 NMR (deuterochloroform) 6 (ppm) Reference substance Tetramethylsilane fine: 1.35 (triplet J = 7 cps) wide: 20 (singlet) 4H: 4.4 ( Quadrut J=7cps) IH: 6.8 (singlet) Fine: 7.3-8.5 (multiplet) 'c'2-[2'-8-thienyl)-6'-chromonyl]propionic acid empirical formula :C, 6th, evening 04: molecular weight = 3
00.31 This compound was prepared analogously to Example b- from the corresponding malonate ester. Melting point of the obtained pale yellow solid = 215-218oo: Yield = 70% Elemental analysis: Calculated value Actual value C% 63.98 64.11 H% 4.03 4.12 S% 10. Iso 10.74 NMR (DMS○d6) 6 (ppm) Reference substance Tetramethylsilane fine: 1.5 (triplet J = 7 cps) IH: 395 (four items J = 7 cps) IH: 7.0 (singlet) Bait: 7.65-865 (multiplet) IH: 12.4-130 (broad peak) Example 16 2-[2-(p-chlorophenyl)-6'-chromonyl]p. Pionic acid [a} Methyl [2-(p-chlorophenyl)
-6-Chromonyl]acetate Empirical formula: C, 8 days, 3C
IQ: Molecular weight = 31856-[2-(p-chlorophenyl)-6-chromonyl]acetic acid (see Example 1) 10.5
The solution was refluxed for 6 hours in 1400 g of anhydrous methanol (0.4 mol) and 70 g of concentrated sulfuric acid. The solution was then filtered and left overnight at 120 qo, and the separated solid was filtered and quickly recrystallized from 2,800 methanol to give a white solid. Yield = 85%: Melting point = 13
5-1370'b-ethyl 2-[2-(p-chlorophenyl)-6-chromonyl]-2-methylmer. Neto empirical formula: C23 days 2, CIQ: Molecular child = 428.
872 50% Sodium Hydride in Mineral Oil 347% (0.872)
0.0725 mol) of ethyl carbonate was heated to 5.0 mol, and methyl (21p-chlorophenyl-6-chromonyl) acetate (0.0
69 mol) was added gradually. The mixture was then refluxed for 2 hours, cooled to room temperature, and a solution of 23.5 moles (0.165 mol) of methyl iodide in dimethylformamide was added dropwise. 2 pieces of the resulting mixture
The precipitate was filtered out and the mother liquor was evaporated to dryness. The solids separated by furnace and the after-clear were mixed, washed with water, and extracted with benzene. The benzene extract was dried, the solvent was removed under reduced pressure, and the yellowish solid residue was recrystallized from diisopropyl ether. Yield = 75%; cocoon turtle point 14 pi○. Elemental analysis: Calculated value Actual value C% 64.41 64. Pine H% 4. Leopard 4.85 CI% 826 815 NMR (Deuterochrome) 6 (ppm) Reference substance Tetramethylsilane Bait: 1.3 (Triplet J:?c
ps) Fine: 2.0 (singlet) Public: 4.3 (quartet J: 7) IH: 685 (around singlet) 7H: 7.4-84 (multiplet) tc} 21 [21 (p-k. Lofenyl)-6'-chromonyl]propionic acid Empirical formula: C, 8 days. 304CI, molecular weight = 328.737 Ethyl 2-[2-(p-chlorophenyl)-6'-chromonyl]-2-methylmalonate 22 (0.07 mol)
A solution of 120 w' of glacial acetic acid and 60 w' of concentrated hydrochloric acid was refluxed for 6 hours. The reaction mixture is then poured into water, the resulting solid is heated,
Dissolved in a 5% solution of sodium bicarbonate. The solution was washed with benzene, separated and acidified, and the resulting solid was recrystallized from isopropanol or toluene. Yield = 60%: melting point 1-185°C. Elemental analysis: Calculated value Actual value C% 65.76 65.91 H% 3.99 4.03 CI% 10.78 10.71 NMR (DMS○d6)8 (ppm) Reference substance Tetramethylsilane 1 3H:1 .5 (double J = 7 cps) IH: 3.95 (quartet J = 7 cps) IH: 7.1
(Singlet) 7H: 7.5-84 (broad peak) IH: 12.1-12.5 (broad peak at 12.3)
Example 172-[2-(o-chlorophenyl)-6'
-Chromonyl]propionate 'a' Methyl [Z-(o
-chlorophenyl)-6'-chromonyl]acetate Empirical formula: C, 8 days, 3CI04: Molecular weight = 3185 This compound is 6-[2-(o-chlorophenyl)chromonyl]
Prepared analogously to Example 18a from acetic acid (see Example 2). A wavy product was thus obtained, which was difficult to crystallize. NMR (carbon tetrachloride) 6 (ppm) Reference substance Tetramethylsilane spot: 3.7 (singlet) IH: 6.5 (around singlet) 7H: 7.3-81 (broad peak) [b} Ethyl 21 [2-(o-chlorophenyl)-
6-Chromonyl]-2-methylmalonate Empirical formula: C2
3 days 2, CIQ; molecular weight = 428.872 This compound was prepared from methyl [o-k.lophenyl-16'-chromonyl] acetate in the same manner as in Example lab-. A yellow oil was thus obtained, which was difficult to crystallize. NMR (
Carbon tetrachloride) 6 (ppm) Reference substance Tetramethylsilane group: 1.2 (triplet J = 7 cps) Spot: 1.9 (singlet) Fly: 4.2 (quartet J = 7 cps) IH: 6.55 (singlet) 7H:7-83 (broad peak) 'c]21[di(〇-chlorophenyl)-6'-chromonyl]propionic acid Empirical formula:
C, 8 days, 304 CI: Molecular weight = 328.737 This compound was prepared analogously to Example 18c} from the product of step 'b'. Melting point of the obtained white solid = 1 - 196°C (toluene)
; Yield = 60% Elemental analysis: Calculated value Actual value C% 6576 65. Spot H% 3.99 4.07 CI% 10.78 10.62 NMR (DMS○d6)6 (ppm) Reference substance Tetramethylsilane: 1.55 (Doublet J=7cps) IH: 4.05 (Quadrut J=7cps) IH:6.7
5 (singlet) 7H: 7-84 (broad peak) IH: 12.5-13.0 (broad peak at 12.75) Example 186-[2-(2,4'-dichlorophenyl)chromonyl] Acetic acid This compound was prepared by method B via the following intermediate.

[a]〆・4″-dichloroZ-hydroxy-5′-methoxymethyl dibenzoylmethane Empirical formula: C, 7 days,
4CI204: Molecular weight = 353. 50% sodium hydride in sea oil 71.5 minutes (1:49
600 moles of dry benzene and 15.7 moles of ethyl 2,4-dichlorobenzoate (0.745 moles) were bagged into a drying reactor. The reaction mixture was brought to reflux and a solution of 89.4 mol (0.496 mol) of 2-hydroxy-5-methoxymethylacetophenone in 280 ml of dry benzene was added over 2 hours. After refluxing for 2 hours to complete the reaction, the mixture was cooled to 3.0 mL. Then, 300 w' of ethanol was added, the alcohol/benzene azeotrope was distilled off under reduced pressure, 2000 w' of 30% acetic acid was added, and the whole was extracted with benzene. The benzene extracts were combined, dried, and the benzene was removed under reduced pressure. The resulting solid residue was dissolved in a 9:1 mixture of alcohol/water at 100%
A yellow solid was obtained by recrystallization from [. Yield = 86%; melting point = 96-10 and 0. 'b} 6-f. Momethyl-2-(2,4'-dichlorophenyl)chromone Empirical formula: C, 6 days 9BrC12Q; molecular weight = 384.
0 porridge step {product of a' 151 times (0.427 mol),
A mixture of 62% HBr470 cucumber and 600 g of glacial acetic acid was heated to 60-70 qo for 3 hours. The resulting mixture was poured into water, filtered, and the separated solid was recrystallized from a mixture of 1700 ml of acetone and 270 ml of dimethylformamide. Yield = 56%: Melting point = 1
61-16〆○ (acetone) elemental analysis: Calculated value Actual value C% 49.96 49.99 H% 2.52 /2.65 CI% 18.43 18.39 (c'6-cyanomethyl-2-(2 ',4'-dichlorophenyl)chromone Empirical formula: C, 7 days 9CI2N02:
Molecular weight = 33095% Potassium cyanide 31.2 (0
．． A solution of 48 moles) in 250 °C of water was heated to 85°C and a solution of the product of step {b} (0.24 moles) in 3900 °C of ethanol was added in 4 portions every 20 minutes. added to. The mixture was refluxed for 3 hours and then evaporated to dryness. The residue was dissolved in 1,000 ml of water, filtered, and the resulting solid was recrystallized from 2,200 ml of a 10:1 mixture of ethanol and dimethylformamide. Yield = 52%: melting point 19
0○. NMR (DMS○d6) 6 (ppm) Reference substance Tetramethylsilane: 4.35 (singlet) IH: 6.80 (singlet) Fine: 7.4-8.7 (broad peak) {d} 6 1 [2-(2,4'-dichlorophenyl)chromonyl)acetic acid Empirical formula: C, 7 days, oC1204; Molecular weight = 349.16 A mixture of 25 parts of acetic acid, 25 parts of concentrated sulfuric acid, and 25 parts of water. 6-cyanomethyl-2-(2.
A solution of 4-dichlorophenyl)chromone (0.03 mol) was refluxed for 3 hours. The solution was then poured into water, heated and dissolved in 500ml of a 5% aqueous solution of sodium bicarbonate. This solution was heated, acidified, filtered again, and the resulting solid was dissolved in a solution of water/acetic acid.
2:8200'. Yield 62%; Melting point =
213-2160. Elemental analysis: Calculated value Actual value C% 58.47 58.48 H% 2.89 2.86 CI% 20.31 20.38 NMR (DMS○d6)6 (ppm) Reference substance Tetramethylsilane 2H:3. 85 (singlet) IH: 6.7 (singlet) Fine: 7.4-8.4 (broad peak) IH: 1-4.5 (broad peak) Example 19 2-[2-(2″・4″-dichlorophenyl)-6′-chromonyl]methyl propionate 61 [21
2,4'-dichlorophenyl)chromonyl]acetate Empirical formula: C, 8 days, 2CI204; Molecular weight = 36 u6-
[2-(2',4'-dichlorophenyl)comonyl]
16.3 ml of acetic acid, 200 ml of methanol and 10 ml of concentrated sulfuric acid
The solution in the solution was refluxed for 6 hours, then cooled and the resulting precipitate was stirred. The precipitate was washed with 500 5% sodium bicarbonate on a table and then with water. Yield = 78%: Melting point = 153oo (ethanol). (b) Ethyl 2-[2-(2″・4″-dichlorophenyl-6-chromonyl]-2-methyl malonate Empirical formula: C23d2oC1206; Molecular weight = 463.317
This compound was produced in the same manner as in Example A). Melting point of the obtained white solid = 11000 (diisopropyl ether): Yield = 65%. NMR (DMS0d6)6
(ppm) Reference substance Tetramethylsilane fine: 1.3 (triplet J = 7 cps) fine: 2.0 (singlet) 4H: 4.3 (quartet J = 7 cps) IH: 6.7 (singlet ) qH: 7.3-8.4 (broad peak) 'c-2-[2'-(2''·4''-dichlorophenyl)-6-chromonyl)propionic acid Empirical formula: C. 8th,
2CI204: Molecular weight=363.19 This compound was prepared from the product of step 'b- in analogy to Example 13b}. Melting point of the obtained white solid = 194-195 qo (toluene); Yield = 60% Elemental analysis: Calculated value Actual value C%
59.52 59.61 H% 3.33 3.30 CI% 19.52 19.48 NMR (DMS○d6)6 (ppm) Reference substance Tetramethylsilane 3H: 1.5 (doublet J=7cps) IH: 3.95 (quartet J = 7 cps) IH: 3-4
(broad peak) IH: 6.65 (singlet) Fine: 7-8.4 (broad peak) Example 20 6-[2-(p-methylphenyl)chromonyl)acetic acid This compound was prepared using method B described in Example 18. It was produced via the following intermediate. (a) 2-Hydroxy-4″-methyl-5′-methoxymethyldibenzoylmethane Empirical formula: C, 8 days.804:
Molecular weight = 2 A yellow solid was obtained by the method described in Example 1, Subsection a'. Yield = 58%: Melting point = 87 to total °C (diisobrobyl ether). {b'2-(4-methylphenyl)-161 furomomethylchromone Empirical formula: C. 7th, 3Br02; molecular weight = 32
A white solid was obtained from the product of step [a-] in the same manner as in Example 9 (Example Skin b). Yield = 60%: Melting point = 197°C (acetone deca dimethylformamide). W 2-(4'-methylphenyl)-6
-Cyanomethylchloride. Mon empirical formula: C, 8 days, 3N02: Molecular weight = 275 A white solid was obtained in the same manner as in step {from the product of b- to Example Lake c}. Yield = 62%: Melting point = 1970 (water/ethanol + dimethylformamide). NMR (DMS○d6) 6 (ppm) Reference substance Tetramethylsilane: 2.4 (singlet) I: 4.25 (around singlet) IH: 7.0 (singlet) 7H: 7.2-8. 3 (broad peak) (d} 6-[2-(p-methylphenyl)chromonyl]acetic acid Empirical formula: C, 8 days, 404: Molecular weight = 294. From the product of step 'c} as in Example step d} A white solid was obtained. Yield = 94%: Melting point = 226-228°C Elemental analysis: Calculated value Actual value C% 73.45 73.22 H% 4.79 4.70 NMR (DMS0d6) 6 (ppm ) Reference substance Tetramethylsilane fine: 2.4 (singlet) 2H: 3.85 (singlet) IH: 7.0 (around singlet) 7H: 7.2-8.4 (broad peak) IH: 11. 7-13.3 (broad peak) Example 2
12-[2-(p-methylphenyl)-6-chromonyl]propionic acid (a} methyl 6-[2-(p-methylphenyl)chromonyl]acetate Empirical formula: C, rainbow,
604: Molecular weight = 308 This compound was produced in the same manner as in Example a). Yield of white solid obtained = 75%: Melting point = 145q0 (
methanol). {b) Ethyl 2-[6-(2'-p-methylphenylphenylchromonyl)]-2-methylmalonate Empirical formula: C24 day 2406: Molecular weight = 408.43 Step {Product of a' to Example 19b}, a pale yellow solid was obtained. Yield = 58%; melting point = 13200. NMR (Deuflochloroform) 6 (ppm) Reference substance Tetramethylsilane mother H: 1.3 (triplet J = 7 cps) 3H: 2.0 (singlet) 3H: 2.45 (singlet) 4H: 4.3 (Quadrut J=7cps) IH: 6.8 (singlet) 7H: 7.2-8.4 (broad peak) [c) 2-[6-(Z-p-methyl phenyl)chromonyl]propionic acid Empirical formula: C, rainbow, 604: molecular weight =
A white solid was obtained analogously to Example 19c) from the product of 3 female 32 step legs. Yield = % mottling; melting point = 196-1°C. Elemental analysis: Calculated value Actual value C% 74.01 73.87 H% 5.23 526 NMR (DMS○d6)6 (ppm) Reference substance Tetramethylsilane group: 1.55 (double J = 7 cps) : 2.40 (singlet) IH: 3.95 (quartet Jcps) IH: 7.0 (singlet) 7H: 7.2-84 (broad peak) Example Ne2-(6'- Flavonyl) propionate'a) Ethyl-2-(6'-flavonyl)-2-methylmalonate Empirical formula: C23 day 2206: Molecular weight = 3 children.
41 Using methyl-6-fraponyl acetate produced in Example 11 as a raw material, a white solid was obtained in the same manner as in Example 13. Yield = Iso%; melting point 99-10 pi (diisopropyl ether). NMR (deutero chloroform) 6 (ppm) Reference substance Tetramethylsilane mother H: 0.9 (triplet J = 7 cps) Pan: 1.6 (-military period) Cape: 39 (four items J = flower ps) IH: 64 (singlet) Amount: 7.2-81 (multiplet) [b'2-(6'-7 laponyl)probionic acid Empirical formula: C, 8th, 404: Molecular weight = 2 groups. A white solid was obtained from the product of Step 29 {a-- in the same manner as in Example 13b-. Yield = 80%; Melting point = 2 °C (acetic acid) Elemental analysis: Calculated value Actual value C% 7346 73. Paper H% 4.79 4. Rudder NMR (DMS0d6) 6 (ppm) Reference substance Tetramethylsilane: 1.6 (double J = reps): 35-4.4 (quartet J: 7 cps) IH: 7.
1 (singlet) Cape: 7.4-84 (multiplet) Example 23 8-diethyl 7minoethyl 2-(6'-flavonyl)
2.95 ml (0.01 mol) of propionate complex 6-flavonyl propionic acid was dissolved in 200 mol of ethanol, and 0.5 mol of potassium dissolved in ethanol was dissolved in 200 mol of ethanol.
A solution of 6 mol (0.01 mol) was added dropwise. The ethanol was then removed under reduced pressure, and the residue was dissolved in 50% acetone. To this solution was added 1.35 g (0.01 mole) of 8-chlorotriethylamine dissolved in 4 parts of acetone, and the mixture was refluxed for 3 hours. The acetone was then evaporated and the pasty afterglow was dissolved in chloroform and water. The organic phase was separated, washed with 5% sodium bicarbonate and then water, dried over sodium sulphate and the solvent was evaporated. The oily residue was dissolved in 50% ethanol,
Salting with sulfuric acid gave a white solid. Yield i70%: melting point = 150-15yo (ethanol). Elemental analysis: Calculated value Actual value C% 63.69 Streak. Departure% 6.20 6.15 N% 2.97 3.03 Example 24 Ethyl 2-(2'-phenyl-6'-coulomonyl)
Propionate empirical formula: C2 rainbow, 804: molecular weight = 32
2.342-(6-Flaponyl)propionic acid 20 minutes (
0.68 mol), concentrated sulfuric acid 2 and anhydrous ethanol lo
The oO mixture was refluxed for 7 hours, then poured into water and extracted multiple times with ether. Ether together. The extract was washed with 5% sodium bicarbonate solution, dried and evaporated to dryness to crystallize the residual oil. Yield = 98%; melting point = 74-7 is o (diisopropyl ether) Elemental analysis: Calculated value Actual value C% 74.52 74.35 H% 5.63 5.75 Example 25 Propyl 2-(2-phenyl ether) 6-Chromonyl)propionate Empirical formula: C2, day 2. 04; Molecular weight = 326.37 This compound was produced in the same manner as in Example 24 by esterification of 2-(6-flavonyl)propionic acid and n-propanol. Yield = 55%; melting point = 59-61°C (hexane). Elemental analysis: Calculated value Actual value C% 74. Nada 75.26 H% 6.00 5.89 Example 26 Isopropyl 2-(2'-phenyl-6'-chromonyl)propionate Empirical formula: C2, day 2. 04; Molecular weight = 336.37 This compound was prepared in the same manner as in Example 24 by esterification of 2-(6'-flavonyl)propionic acid and isopropanol. Yield = 80%; melting point = 78-80qC (diisopropyl ether). Elemental analysis: Calculated value Actual value C% 74.98 74.64 H% 6.00 5.97 Example 27 Butyl 2-(2-phenyl-6-chromonyl)propionate Empirical formula: C22 day 2204: Molecular weight = 350.
40 A white solid was obtained in the same manner as in Example 24. Yield = 80%; Melting point = 44-46qo (hexane) Elemental analysis: Calculated value Actual value C% 75.40 75.22 H% 6.33 6.35 Example 28 8-Hydroxyethyl 2-(2-phenyl) 6'-chromonyl)propionate-hydrate Day 20 Empirical formula: C2
Rainbow 2o06: Molecular weight = 356.362 A mixture of 11.8 moles (0.04 moles) of mono(6'-flavonyl)propionic acid, 100 moles of benzene, 100 moles of ethylene glycol, and 1.35 moles of p-toluenesulfonic acid was diluted. Refluxed for 4 hours in a flask equipped with an And Stark apparatus. The reaction mixture was then poured into water and the oil that separated was crushed and crystallized to give a white solid. Yield = 90%:
Melting point = 79-8 Ti○ (10:6 of hexane and ethyl acetate)
blend). Elemental analysis: Calculated value Actual value C% 67.40 67.22 H% 6.66 5.52 Example 29 Methyl 21[21(Q-thienyl)-6-chromonyl]propionate Empirical formula: C, 7 days, 4S04: Molecular weight = 314.34 This compound was prepared in the same manner as in Example 24 by esterifying the acid of Example 13 and methanol in the presence of sulfuric acid. Yield = 80%: Melting point = 96-Satoshi (ethyl acetate). Elemental analysis: Calculated value Actual value C% 64.96 65.24 H% 4.49 4.27 S% 10.20 10.28 Example 30 Methyl 2-(2-(8-thienyl)-6-chromonyl)propionate Empirical formula: C, 7 days, 4S04: Molecular weight = 314.34 This compound was prepared in the same manner as in Example 24 by esterifying the acid of Example 15 and methanol in the presence of sulfuric acid. Yield = 85 Melting point = 95~Satoshi (diisopropyl ether). Elemental analysis: Calculated value Actual value C% 64.95 65.10 H% 4.49 4.47 S% 10.20 10.20 Example 31 Propyl 2-( 2'-Q-thienyl-6-chromonyl)propionate Empirical formula: C, Rainbow, 804S; Molecular weight =
343.33 This compound was prepared from the acid of Example 13 in Example 2.
It was manufactured in the same manner as 5. The melting point of the white solid obtained was 48-520. Yield = 90%
. Elemental analysis: Calculated value Actual value C% 66.66 66.47 H% 5.29 5.27 S% 9.36 9.40 Example 32 8-morpholinoethyl-21 [21 (Q-thienyl-6
-Hakamate salt empirical formula of chromonyl]propionate: C24
25NO9S: Molecular weight = 503.52-[2'-[Q
A mixture of 12 (0.04 moles) potassium, 2.55 moles (0.04 moles) of potassium, and 500 moles of methanol was refluxed for 30 minutes, the solvent was distilled off under reduced pressure, and a powder was obtained. 500' of methyl isobutyl ketone and freshly distilled chloroethyl
The mixture was refluxed for 8 hours in 10.5 liters of morpholine and the resulting solid was filtered off. The methyl isobutyl ketone was then removed from the organic phase in vacuo, and the oil was quickly salified with Hakama acid dissolved in acetone. The resulting salt was prepared by recrystallization from a 6:1 mixture of acetone/water. . Yield = 70%, melting point = 167-170°C (
ethanol). Elemental analysis: Calculated value Actual value C% 57.25 57.27 H% 5.00 4.97 N% 2.78 2.71 S% 6.36 6.10 Example 33 6-[2-(2' -Phenoxyphenyl)-chromonyl]acetic acid This compound was prepared in the same manner as in Example 18 via the following intermediates. 'a'2'-Hydroxy-2''-phenoxy5'-methoxymethyl dibenzoyl methane Empirical formula: C23 Day 2.05; Molecular weight = 376.39 A yellow solid was obtained in the same manner as in Example A. Yield = 75%. ; Melting point = 94oo (diisopropyl ether). (b} 2-(2'-phenoxy phenyl)-
6-Furomo Methylchromone Empirical formula: C2 Rainbow, PrQ:
Molecular weight=407.25 A white solid was obtained in the same manner as in Example b'. Yield = 71%: Melting point = 145oo (acetone). [c'
2-(2-phenoxyphenol)-161 cyanomethylchromone Empirical formula: C23, 5N03; Molecular weight = 35
3.35 A white solid was obtained in the same manner as in Example 1. Yield = 38%: Melting point = 138oo (ethanol'.'d
} 6-[2-(2-phenoxyphenyl)chromonyl]acetic acid Empirical formula: C23 days, 605; Molecular weight = 372.
36 Example 1 Shoes d} A white solid was obtained. Yield; 63%: melting point = 170 (ethanol). NMR (
Deutero chloroform) 6 (ppm) Reference substance Tetramethylsilane 2H: 3.8 (singlet) IH: 5.2-5.5 (broad peak) 13H: 6.9-8.3 (broad peak) Example 34 2-[2-Mephenoxyphenyl)-6'-chromonyl]propionic acid {a-methyl 6-[2-(2'
-Phenoxy phenyl) chromonyl]acetate Empirical formula: C24 days, 805: Molecular weight = 386. Class example 19
A white solid was obtained in the same manner as in step a}. Yield = 65%: Melting point = 12yo (methanol). (b)
Ethyl 2-[2-(2″-phenoxy phenyl)-chromonyl-2-methyl malonate Empirical formula: C2pan2
607: Molecular weight = 486.50 A brown oil was obtained in the same manner as in Example 19'b'. This could not be crystallized.
Yield = 58%. NMR (Deubro Chloroform) 6
(ppm) Reference substance Tetramethylsilane mother H: 1.3 (triplet J = 7 cps) 9H: 1.9 (singlet) H: 4.2 (quartet J = 7 cps) 1-fold: 6.8 ~8.1 (broad peak) 'c} 2-[2-(2″-phenoxy phenyl)-
6-chromonyl]propionic acid empirical formula: C24 days, 80
5; Molecular weight = 386. A white solid was obtained in the same manner as in Spotted Example 19c'. Yield = 50%; melting point = 175-178 qo (isopropanol). NMR (DMS○d6) 6 (ppm) Reference substance Tetramethylsilane: 1,55 (double J = 7 cps) Wide range: 3.8 to 4.2 (quadruple J = 7 cps wide range)
1st pan: 6.9-8.2 (broad peak) Elemental analysis: Calculated value Actual value C% 74.60 74.35 H% 4.69 4.51 Example 35 2-[2'-(3''- trifluoromethyl phenyl)
-6-chromonyl]p. Pionic acid (a-methyl [2-(3-trifluoromethyl phenyl)-6-chromonyl] acetate empirical formula:
C, Rainbow, 3F304: Molecular weight = 361 This compound is 6-
(2-m-trifluoromethyl phenyl chromonyl) Prepared analogously to Example 19a} by esterification of acetic acid in the presence of sulfuric acid. Yield = 83%: melting point 14000 (methanol) NMR (
DMS○d6) 6 (ppm) Reference substance Tetramethylsilane 9H: 3.30 (singlet) 2H: 3.40 (around singlet) IH: 6.65 (singlet) 7H: 7.20-8.00 ( (b) Ethyl 2-[2'-(3''-trifluoromethyl phenyl)-6'-chromonyl]12-methyl
Malonate empirical formula: C24 day 2, F306: molecular weight = 4
62.41 A white solid was obtained analogously to Example 19b). Yield = 64%: Melting point = 82-8gO (diisopropyl ether). NMR (carbon tetrachloride) 6 (ppm) Reference substance Tetramethylsilane mother H: 1.3 (triplet J = 7 cps) 3H: 1.9 (singlet) H: 4.2 (quartet J = 7 cps) ) IH: 6.8 (singlet) 7H: 7.3-8.3 (multiplet) (c} 21 [21 (3″-trifluoro methyl phenyl)-6-chromonyl] propionic acid Empirical formula: C,
304F3: Molecular weight = 362.19 Example 19c}
A white solid was obtained in the same manner as above. Yield = 60%: Melting point 71-17yo (toluene) Elemental analysis: Calculated value Actual value C% 63.00 63.16 H% 3.62 3.56 F% 1574 15.82 NMR (DMS○d6) 6( ppm) Reference substance Tetramethylsilane crude: 1.6 (doublet J = 7 cps) general: 3.4 to 4.4 (quartet J = 7 cps) IH: 7
．． 3 (singlet) 7H: 7.8-8.6 (multiplet)

Claims (1)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound of (in the formula, X has the meaning below) is esterified with methanol, and the obtained methyl ester is esterified with diethyl carbonate and hydrogen. General formula consisting of conversion to the corresponding ethyl malonate by treatment with sodium chloride, alkylation of the carbanion with methyl iodide in dimethylformamide, followed by acid hydrolysis and decarboxylation of the malonic acid: , chemical formulas, tables, etc. of chromonyl-substituted propionic acids (wherein X is a phenyl, furyl or thienyl group substituted by at least one halogen, lower alkyl, trihalomethyl or aryloxy group) Production method. 2 General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound of (in the formula, X has the meaning below) is esterified with methanol, and the obtained methyl ester is treated with diethyl carbonate and sodium hydride. The carbanion is converted to the corresponding ethyl malonate, and the carbanion is alkylated with methyl iodide in dimethylformamide, followed by acid hydrolysis and decarboxylation of malonic acid to give the general formula: ▲Mathematical formula, chemical formula, table, etc. ▼ General formula consisting of forming a chromonyl-substituted propionic acid of (wherein X has the meaning given below) and reacting it with an alcohol of the formula ROH (wherein X has the meaning given below): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, ω-hydroxy lower alkyl,
A method for producing a chromonyl-substituted propionate ester of dialkylamino lower alkyl or morpholinoethyl group.